Indian J Otolaryngol Head Neck Surg
(October 2019) 71(Suppl 1):S439–S446; https://doi.org/10.1007/s12070-018-1345-0
ORIGINAL ARTICLE
Xanthelasma Palpebrarum: More than Meets the Eye
Shailesh Khode1 • Soon Heng Terry Tan1 • En-Pei Amanda Tan1
Sandeep Uppal1
Received: 19 September 2017 / Accepted: 5 April 2018 / Published online: 7 April 2018
Ó Association of Otolaryngologists of India 2018
Abstract Xanthelasma palpebrarum (XP) is the most
common form of cutaneous xanthomata, and is important
aesthetically, because of its close relation to the eyes, as
well as medically for its association with cardiovascular
disease (CVD). To provide avant-garde review discussing
the various aspects of XP, including its aetio-pathogenesis
and various treatment modalities. A structured Pubmed and
Medline were searched for relevant articles. The finding of
recent research has strongly espoused the link between XP
and CVD, and mechanisms have been suggested for its
formation. The new technologies have led to a multitude of
treatment options for XP. XP is a multi-faceted entity;
other than simple treatment of the cosmetic aspect of the
disease, one must be cognizant of its cardiovascular
implications.
Keywords Xanthelasma palpebrarum
Lipid

Cardiovascular disease
Tri-chloroacetic acid
Laser

Blepharoplasty
& Shailesh Khode
shaileshkhode@gmail.com
Soon Heng Terry Tan
tan.terry.sh@ktph.com.sg
En-Pei Amanda Tan
tan.amanda.ep@ktph.com.sg
Sandeep Uppal
uppal.sandeep@ktph.com.sg
1 and there may be surrounding inflammation and fibrosis.
Department of Otolaryngology – Head and Neck Surgery,
Khoo Teck Puat Hospital, 90 Yishun Central, Yishun 768828,
Singapore
•
Introduction
Xanthelasma palpebrarum (XP) is the most common form
of cutaneous xanthomata [1, 2], so called because of its
location close to the eye. It is derived from the Greek
words, xanthos which means yellow and elasma which is a
beaten metal plate. It is more commonly seen in middle-
aged to elderly adults, with an incidence of 0.3% in males
and 1.1% in females [3]. It is not a disease of modern
times; the painting of Mona Lisa by Leonardo da Vinci
(1503–1506) represents possibly the first recorded evidence
of XP, as suggested by Dequeker et al. [4].
Patients often present to their doctor because of cos-
metic concerns and request treatment of these aesthetically
undesirable lesions in a prominent part of their face.
Lesions are typically raised, soft, yellowish, irregularly
shaped plaques that are slow growing, and are usually
found over the medial aspect of the eye [1, 2]. They can
also be found over the upper and lower eyelids, and cir-
cumferential lesions have been described [5]. The doctor
not only needs to address the aesthetic concerns of the
patient, but also needs to be cognizant of the aetiopatho-
genesis of this condition and its association with
atherosclerotic cardiovascular disease (CVD).
Histopathology
Xanthelasma comprises mainly of perivascular and peri-
adnexal foamy histiocytes and occasional Touton giant
cells in the upper and middle dermis [6], giving a macro-
scopic appearance of an unsightly soft, yellowish plaque.
The intracellular vacuoles contain esterified cholesterol,
Lymphocytes and mast cells [7] are common components
of the inflammatory matrix. There appear to be similarities
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in the ultra-structural makeup of xanthomata and evolving
atheromas, for instance between the intimal smooth muscle
cells of arteries and the perithelial cells of dermal capil-
laries, hence suggesting that analogous mechanisms may
be involved [8, 9]. There is variation in terms of the
extensiveness of involvement, with the upper eyelid and
medial canthus frequently affected. The fact that the peri-
ocular region is preferentially affected implies that local
factors, such as constant movement and friction, may play
a role in its pathogenesis, though its mechanism is not well
elucidated.
Aetiopathogenesis and Prevalence
While XP is usually diagnosed by clinical appearance
alone, it may be an important marker of underlying disease.
It is present in a fair proportion of patients with familial
hyperlipoproteinemia, most frequently the type-IIa
Fredrickson phenotype [10–12]. It is classically associated
with an increased risk of atherosclerotic CVD. Hence it is
generally recommended that patients with XP should at
least have a basic lipid screen, including low and high-
density lipoprotein (LDL and HDL) levels. Reported
prevalence of atherosclerotic CVD amongst XP patients
have been varied, with numbers ranging from 15 to 70%
[11, 13–16]. Conversely other studies have found little or
no increase in the risk of atherosclerosis [12]. This wide
range may be attributed to limitations and differences in
methodology over the years [1, 17].
Association Between Xanthelasmata,
Hyperlipidemia and Cardiovascular Disease
Although many patients with XP have raised total choles-
terol levels, up to half of these may have normal lipid
levels. While it is generally accepted that xanthelasmata in
hyperlipidemic patients are associated with higher LDL
and lower HDL levels, both of which are established
atherogenic risk factors, the reasons behind the evolution of
xanthelasma in normolipidemic patients remain more
obscure. Possible implicating factors other than hyper-
lipoproteinemia include increased vascular lipid perme-
ability, lipid synthesis and macrophagic uptake [18]. Other
apolipoproteins have been shown to be associated with XP
formation, though not conclusively. For instance,
apolipoprotein B (Apo-B), a marker of atherosclerotic
CVD, was reported to be elevated in normolipidemic XP
patients by Douste-Blazy et al. [19], but not so by Gomez
et al. [12] Likewise, Douste-Blazy et al. [19] too found
increased prevalence of apolipoprotein E2 and E3 pheno-
types in normolipidemic XP patients, but the results were
not replicated by Gomez et al. [12].
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More recently carotid intima media thickness measure-
ments (CIMT) are accepted as a surrogate marker for
generalised atherosclerosis and risk of CVD [20]. Noel [21]
was one of the first to evaluate CIMT in patients with XP,
and found an increase in mean CIMT values in patients
with XP compared to controls. Pandhi et al. [22] found the
same results in his study involving BMI matched controls,
and went on to conclude that XP may be a risk factor for
atherosclerosis regardless of the patient’s lipid levels.
There was, however, no correlation with the duration or
extent of the lesion. Another index of arterial stiffness is
cardio-ankle vascular index (CAVI) which is significant
marker for sub-clinical atherosclerosis. Akyuz A R et al.
investigated the association between CAVI and XP, and
concluded that XP was an independent predictor for
abnormal CAVI [23].
Other Associations of Xantholesma
Besides lipid abnormalities, XP has also been associated
with allergic contact dermatitis, periorbital hyperpigmen-
tation, smoking and obesity [24, 25]. XP can also develop
following surgical procedures such as injection fillers [26],
and septorhinoplasty [27] (See Table 1). An inflammatory
mechanism with resultant vascular permeability and
oedema has been proposed [28]. Local trauma has been
shown to increase capillary leakage of LDLs, and xan-
thomas are a result of subsequent inflammatory reactions.
For instance, hyaluronic acid from injections in the extra-
cellular matrix can bind extravasated LDL, and this LDL-
glycosaminoglycan complex is taken up more easily by
macrophages than native LDL [29]. Furthermore, gly-
cosaminoglycans promote the oxidation of LDLs, which in
turn leads to foam cell formation. Nilotinib, a tyrosine
kinase inhibitor used in the treatment of chronic myloid
leukemia is also believed to cause both lipid panel abnor-
malities and cutaneous lesions [30].
Treatment Options
Until about 30 years ago, XPs were only effectively
removed by surgery with cold steel instruments [31].
Although, meticulous percutaneous resection of the lesions
followed by direct suture has remained one of the more
popular techniques, the high risk of recurrence and other
complications like ectropion are among the reasons which
have drawn surgeons to seek alternative methods of
removal. The relative paucity of skin at the lower lid means
that repeated resections of recurrences may not be possible
if cosmesis is to be preserved [32], hence the search for
skin sparing techniques. With the advent of medical tech-
nology and research, a plethora of options has surfaced
(See Table 2).
Indian J Otolaryngol Head Neck Surg (October 2019) 71(Suppl 1):S439–S446
Table 1 Clinico-pathological conditions associated with xanthe-
lasma palpebrarum [10–12, 24–30]
Clinico-pathological conditions
Familial hyperlipoproteinemia
Macrophage abnormalities
Allergic contact dermatitis
Periorbital hyperpigmentation
Smoking
Obesity
Injection of intradermal hyaluronic acid fillers
Post septorhinoplasty
A new side effect of Nilotinib
Surgical Excision
Hoon Young Lee et al. graded XP into four types, on basis
of location and extent of lesion. Grade I lesions involve
only the upper eyelids; grade II extends to the medial
canthal area; grade III involves medial side of both upper
and lower eyelids, and grade IV ones have diffuse
involvement of the medial and lateral side of both upper
and lower eyelids. Hoon treated grade I and II lesions by
simple excision while grade III and IV ones were managed
by excision in combination with skin grafting, local flaps,
blepharoplasty and medial epicanthoplasty [33]. Similarly,
Kose R treated large XP defects with full thickness skin
grafts harvested from the lateral aspect of the upper eyelid.
Good patient satisfaction was achieved by performing
blepharoplasty of the upper eyelid simultaneously with the
excision of XPs [34]. Authors suggested that for lesions
involving the deep dermis and/or muscle, cold steel dis-
section may be the most suitable treatment option (Fig. 1).
Di- and Tri-Chloroacetic Acids (DCA and TCA)
These chemicals have been described in the treatment of
XP. They are chlorinated acetic acids, and are used in
different concentrations as tissue cauterants [35]. They
work by dissolving lipids and coagulating proteins. A thin
layer is applied over the lesion with a wooden applicator
stick, with care taken to avoid the surrounding healthy skin.
Blanching will subsequently be observed, and antibiotic
creams are then applied. Side effects associated with this
form of treatment include hypo- and hyperpigmentation,
scarring and accidental application to the conjunctiva or
cornea. Haygood et al. [36] treated 25 patients with 100%
Bichloracetic acid (BCA), with 85% of them achieving
initial complete clearance. The other 28% of the lesions
required repeated application after an average period of
64 months, but these recurrences generally responded well
to retreatment. TCA has increased in popularity recently,
S441
with different concentrations trialed. Cannon et al. [37]
investigated the efficacy of 95% TCA in a retrospective
review of 102 patients, of which 44 and 51 patients were
examined clinically and interviewed respectively. They
found a limited success rate of 61% at a mean follow up of
31.8 months. Hague and Ramesh [38] used varying con-
centrations (50, 70 and 100%) of TCA on 51 patients, and
commented that higher concentrations worked better with
papulo-nodular lesions and flat plaques, while 50% TCA
was sufficient for macular lesions. However the duration of
follow-up was not cited. In a study of 24 patients treated
with 70% TCA, Nahas et al. [39] found that an average of
1.5 applications was required to treat till resolution and
25% of lesions had recurrence 6 months after treatment.
Nonetheless, patient satisfaction was high, making this an
attractive, simple and low-cost viable alternative for the
treatment of XPs.
Low Voltage Radiofrequency
Radiofrequency works by causing vaporization at a cellular
level in tissues. It initiates fibrosis followed by volume
reduction during healing. This novel technique has been
attempted by Dincer et al., on 15 patients. A dual-fre-
quency radiofrequency machine was used at low power
settings. Electrodes were applied superficially onto the
lesions under local anaesthesia, following which creams
were applied to reduce the risk of infection and hasten re-
epithelialization. Pateints were followed up for 5 months,
and success was graded according to a subjective 5 point
scale (0 = no result, 0–25% Mild, 26–50% = moderate,
51–75% = good, and 76–100% = excellent). Preliminary
results were promising, with 14 patients having at least a
‘good’ (second best) result. Of the 15 patients who were
treated this way, 5 required a second session to achieve a
satisfactory result. Main complications were pain, and
hyper- or hypopigmentation. This technique is potentially a
quick, inexpensive and relatively safe therapeutic modality.
The authors recommended that it may be useful in cases
where there are multiple lesions; lesions have indistinct
borders or are situated close to the eyes [40].
Cryotherapy
Cryotherapy works by one or more of the following ways:
ice crystal formation, thermal shock, enzyme inhibition,
cellular dehydration and electrolyte disruption [41–43].
Dewan et al. [44] looked at 100 patients with a total of 237
lesions, and performed closed probe cryosurgery with
nitrous oxide as the cryogen, without local anaesthesia.
Freezing time was 15 s, and the number of freeze–thaw
cycles ranged from 1 to 21 depending on the size and
number of lesions. Follow up was set at 6 months, which
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S442 Indian J Otolaryngol Head Neck Surg (October 2019) 71(Suppl 1):S439–S446

Table 2 Different modalities of treatment for XPs

Modality of treatment Principle No. of session Advantage Side effects

Surgical excision [33, 34] Meticulous percutaneous One or Simple Recurrence,

resection of the lesions revision Best for lesion involving deep Ectropion
followed by direct suture surgery dermis and muscle Scar contracture
with or without flap
Combined with blepharoplasty Revision surgery
TCA peeling (concentration Dissolving lipids and 1–12 Simple Hypo- and Hyper-pigmentation
35–100%) [35–39] coagulating proteins Low-cost Scarring
Out-patient clinic procedure Accidental application to the
conjunctiva or cornea—
atrophy,
Koebner-like phenomenon
Low/Mid Voltage Thermal energy induces Single Quick, Hypo- and Hyper-pigmentation
Radiofrequency [40] vaporization at the cellular Inexpensive Pain
level in tissues
Relatively safe
Cryo-surgery (nitrous oxide) Ice crystal formation, Cellular 1–21 Cycle Easy for application Recurrence,
[44, 45] dehydration and electrolyte Low risk of adverse effects Hypopigmentation
disruption, Thermal shock,
Healing is slow
Enzyme inhibition or Effect
on proteins Extensive lesions are difficult
to treat
CO2 laser (ultra pulse) Absorbed by the extracellular 1–5 Sessions Less downtime, Hyperpigmentation, scaring,
(10,600 nm) [47–50] fluid of tissue cells, leading High patient satisfaction recurrence
to non-specific vaporisation
Erbium:YAG laser Absorption by water- Single Suitable for early lesion Mild erythema.
(2940 nm) [51–55] containing tissues Hypo- and Hyper-pigmentation
Nd:YAG laser (1064 nm) Q-switched—cellular Single Large lesions Erythema
[56–59] fragmentation via shock
waves
KPT laser (532 nm) [60, 61] Continuous wave Single Safe Hypopigmentation,
Recurrences
Diode laser (1450 nm) Preferentially targets water Single Satisfactory result Transient focal
[66, 67] hyperpigmentation
Pulsed dye laser (585 nm) Vascular specific, targeting 5 Sessions High patient satisfaction Blisters, crusting and ectropion
[31, 62] small vessels
Intra-lesional A broad-spectrum antitumor 1 Session Cheap, effective, and safe No complications
Pingyangmycin [73] antibiotic

showed that 68% of the cases had complete resolution of
the lesions and 6% had incomplete resolution, with a tiny
central area of hypopigmentation. The other 26% had
either persistence or recurrence of the lesion. Labanderia
et al. treated four cases of XPs with gentle liquid nitrogen
spray cryotherapy. This treatment modality was advocated
because of its easy applicability and minimal adverse
effects [45].
Laser Therapy
Laser vaporisation is the latest technique in the treatment
of XP. Within this category, the different lasers with their
varying wavelengths and properties, coupled with a
multitude of surgical techniques, give rise to an interesting
range of treatment options [46].
Ablative Lasers
Carbon dioxide (CO2) lasers are one of most widely uti-
lised lasers in the medical arena. Its 10,600 nm wavelength
means that it is selectively absorbed by the extracellular
fluid of tissue cells, leading to non-specific vaporisation,
regardless of pigmentation. It is an ablative laser, hence the
need for some form of anaesthesia during the procedure. It
results in an open wound, therefore the need for wound
care and dressing post-operatively. Its ablative effect,
especially in the continuous mode, may result in collateral
tissue damage leading to unpredictable scarring and

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Indian J Otolaryngol Head Neck Surg (October 2019) 71(Suppl 1):S439–S446
Fig. 1 a, b (Pre-operative) and c, d (post operative) clinical
photographs of a patient presenting with xanthelasma palpebrarum
involving the left upper lid
asymmetrical skin retractions. With current technology, it
has become possible to deliver high energy beams in
extremely short impulses, beyond the skin thermal relax-
ation time. This ultrapulsed CO2 laser allows for more
precise ablation of skin layers and less injury to the sur-
rounding tissues. Raulin et al. [47] treated 23 patients (52
lesions) with the ultrapulsed CO2 laser with good effect,
removing all lesions with a single treatment. Pigmentary
changes were transient, seen in 17% of cases, without
visible scarring. Three patients developed a recurrence,
which the authors postulated may be due to an inadequate
depth of treatment. Pathania et al. and Saif MYS et al.
[48, 49] achieved similarly good results. A randomized
control trial was conducted by Esmat et al. to compare the
efficacy and safety of super pulsed (SP) and fractional CO2
laser in 20 adult patients with bilaterally symmetrical XPs.
Randomly assigned XP lesions were treated with one ses-
sion of super pulsed CO2 laser or 3–5 sessions of fractional
CO2 laser. After removal, XP lesion on both sides showed
remarkable improvement in size, colour and thickness of
lesions. The lesions treated with SP CO2 laser showed
significant improvement in colour and thickness of lesions.
Nevertheless, better patient satisfaction and shorter time-
out was observed with fractional CO2 laser [50].
The erbium:YAG laser is another form of ablative laser
that has been tried. It has a wavelength of 2940 nm, with
preferential absorption by water-containing tissues. It is
S443
less invasive compared to the conventional CO2 laser,
making it possible to ablate thin layers of skin to a depth of
a few nanometers, hence allowing for precise manipulation
with less damage to surrounding healthy tissues. Post-
treatment complications are also minimised because of the
non-invasive nature of this laser, with erythema disap-
pearing after 2 weeks for most patients. Borelli and
Kaudewitz [51] treated 33 lesions in 15 patients and noted
no recurrence in a follow-up period of 7–12 months. They
concluded that this laser was a minimally invasive method
suitable for treating early lesions before they become aes-
thetically problematic. In addition, he commented on the
merits of the CO2 laser, for instance, better hemostasis and
allowed for removal of deeper lesions which were also
documented by Mannino et al. [52], Kaufman and Hibst
[53], and Drnovsek-Olup and Vedlin [54] in 70 XPs, 9XPs
and 32 XPs respectively. Levy and Trelles [55] described
an inverted resurfacing technique with the erbium:YAG
laser, whereby the eyelid skin is everted, exposing the
lesional tissue and orbicularis oculi. The lesion is then
precisely vaporised with the laser until normal tissue
architecture is seen, following which the skin flaps are
replaced and closed.
Non-ablative Lasers
Non-ablative lasers are gaining favour in recent years due
to their non-invasive properties, safety profile, and possi-
bility of using them in office based procedures. The
1064 nm Q-switched Nd:YAG laser has been in use since
the 1990s for the treatment of tattoo and pigmented lesions.
The mechanism of action is cellular fragmentation via
shock waves generated from sudden energy transfer, con-
finement and release in a photoacoustic phenomenon [56].
Fusade [57] treated 38 lesions in 11 patients with this laser,
and obtained good to excellent results (defined as 50% or
more clearing) in 26 lesions. On the contrary, Karsai et al.
[58] could not replicate Fusade’s results, getting instead a
high dropout rate (due largely to apparent inefficacy) and
low success rate (70–75% of treated lesions showed no
clearance). However, later, Leonardo Marini treated 20
periocular XPs in twelve patients, all achieving at least
good outcomes, defined as more than 50% clearance [59].
Another non-ablative laser is the KTP (Potassium Tita-
nyl Phosphate) laser. It has a wavelength of 532 nm and
was first time introduced by Berger C and Kopera D in the
treatment of XP. They treated 33 lesions in 14 patients.
After one to three sessions 86% patients showed convinc-
ing reduction of XPs without side effects. Moreover, 70%
of patients tolerated procedure without any anaesthesia
[60]. Recently a retrospective study was conducted by
Greijimans et al. to evaluate the safety and efficacy of
continuous wave KTP laser treatment for XPs. Overall,
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S444 Indian J Otolaryngol Head Neck Surg (October 2019) 71(Suppl 1):S439–S446
97% (29/30) patient had excellent aesthetic results. How-
ever, recurrences were frequent (43%; 13/30) which war-
ranted regular maintenance therapy [61].
The pulsed dye laser (PDL) was first described by
Schönermark and Raulin [62], and had been used to some
success by Karsai et al. [31]. In his prospective clinical trial
of 38 cases (in 20 patients), a 585 nm wavelength laser was
utilised. The laser is vascular specific, targeting small
vessels to which the offending histiocytes are adherent to,
thereby simultaneously causing the destruction of these
cells. The 20 patients underwent five sessions with the
laser, after which pre- and post-operative photographs were
compared and assessed by independent examiners. Two-
thirds of lesions showed clearance of more than 50%, while
one-quarter had clearance of more than 75%. Patient sat-
isfaction was high, and there were no major side effects
like blisters, crusting and ectropion. Karsai et al. [31]
suggested that a combination of ablative and non-ablative
laser therapy holds promise in the removal of tuberous
lesions.
Other kinds of lasers that have been utilised in recent
years include the 1450 nm diode laser. It preferentially
targets water, causing photothermal destruction of seba-
ceous lobules and hair follicles, up to 500 lm in depth
[63]. It has been used for the number of years, safely and
efficaciously, for a number of skin lesions including acne
[63, 64], sebaceous hyperplasia [65] and scarring [66]. Its
exact mechanism in the treatment of xanthelasma is not
well elucidated, but it is believed that the foamy histiocytes
are targeted by the 1450 nm wavelength energy emission.
Park et al. [67] used it to good effect in 16 patients, with
75% achieving moderate to marked clearance (defined as
more than 40%) after one to four sessions. Transient focal
hyperpigmentation was the most common post-operative
side effect, occurring in five patients.
Other Treatment Modalities
Non-surgical treatment of XP has limited applicability. A
decade ago, Shields et al. published an observational case
report on the disappearance of XP following oral simvas-
tatin. They postulated that oral statins combined with a fat
restricted diet might result in resolution of XP, and
reduction in cardiac risk, especially in young patients [68].
A novel technique was introduced by Wang et al., making
use of Pingyangmycin which is a broad spectrum antitumor
antibiotic. Twenty-one lesions in 12 patients were treated
by intralesional infiltration of this antibiotic. All patient
except one achieved satisfactory result after 2 sessions
without any complications like infection, atrophy, ulcera-
tion or scarring [69].
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Discussion
Few studies have been published in literature comparing
different modalities of treatment for XPs. Mourad B and
colleagues assessed the clinical efficacy and tolerability of
different concentration of topical TCA (35, 50, and 70%)
against CO2 laser in 30 XPs. Both 70% TCA peeling and
CO2 laser ablation demonstrated more significant clinical
efficacy and patient satisfaction with minimum number of
treatment sessions than 35 and 50% TCA peeling [70].
Similarly, a prospective study comparing ultra-pulsed CO2
laser and 30% TCU was conducted by Goel K et al. It
suggested that both TCA and lasers are good for clinically
small lesions but the laser works more effectively in severe
lesions [71]. Another comparative study was conducted by
Mona Abdelkader et al., this time comparing argon laser
against the erbium: YAG laser. Thus concluded that former
was good for small lesions while the later was better for
larger nodular lesion [72]. On the other hand, Gungor S and
co-workers documented no significant difference in the
post treatment improvement scores as well as complication
scores for both Erbium:YAG laser ablation and 70% TCA
application [73].
Overall, some authors have suggested that surgical
excision of deep dermal and/or muscle XPs may be the
most suitable modality of treatment in experienced hands.
Higher concentrated TCA in papulo-nodular XP lesions
and 50% TCA in macular lesions showed promising
results. XPs near the lid margin or close to the canthus can
be managed safely with low voltage radiofrequency. Lat-
terly, non-ablative lasers are well accepted more by
patients as well as physicians because of their minimal side
effects, desirable outcomes and may be performed as out-
patient clinic procedures.
Conclusion
There is a myriad of options available for the treatment of
XP, but thus far, a preferred modality has not emerged, as
no one method has been shown to be irrefutably superior to
the rest. Furthermore, only a limited number of comparison
studies have been done, and they are relatively small with
short follow-up durations [38, 68–71]. More research and
development, as well as well-designed large prospective
trials, will be needed to further our knowledge in this area
of medicine. However, other than just treating the aesthetic
aspect of this condition, one must be aware of its cardio-
vascular implications, thus allowing for holistic manage-
ment of the patient.
Indian J Otolaryngol Head Neck Surg (October 2019) 71(Suppl 1):S439–S446
Compliance with Ethical Standards
Conflict of interest The authors declare that they have no conflict of
interest.
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